Immuno-suppressive peptides for a human T cell clone autoreactive to a unique acetylcholine receptor alpha subunit peptide presented by the disease-susceptible HLA-DQ6 in infant-onset myasthenia gravis.
Infant-onset myasthenia gravis, an autoimmune disease specific to Asians predominantly affects neuromuscular junctions in ocular muscles. An AChR alpha peptide (p71-91) specific autoreactive CD4+ alpha beta T cell clone was established by stimulating PBMC from a patient heterozygous for two disease-susceptible HLA-DR9-DQ9 and DR13-DQ6 haplotypes with a mixture of overlapping peptides covering AChR alpha. The T cell clone recognized the AChR alpha peptide in the context of the HLA-DQ6 molecule and produced a large amount of IFN-gamma and a trace amount of IL-4. A part (p75-83) of the core epitope of the autoantigenic peptide (p75-87) is encoded for by an exon P3A of the AChR alpha gene which can be alternatively spliced. The T cell clone responded to the recombinant AChR alpha protein with a P3A exon product, but not without a P3A exon product. We investigated responses of the T cell clone to 114 analogue peptides carrying single residue substitutions of the core AChR alpha peptide. The majority of analogues substituted at residues Phe-77, Leu-80 and Asn-82 stimulated proliferation of the T cell clone. Conversely, the majority of analogue peptides substituted at either Gln-81 or Glu-83 did not stimulate proliferative responses, and all exhibited strong or intermediate inhibitory effects on proliferative responses of the T cell clone to the wild type peptide, possibly by TCR antagonism. Thus, an HLA class II allele specific to Asians may directly control susceptibility to the Asian-specific type of myasthenia gravis. Analogues of the auto-antigenic AChR alpha peptide may prove effective for new immunosuppressive therapy.
Kanai
T
T
Department of Neuroscience and Immunology, Kumamoto University Graduate School of Medical Sciences, Japan.
Nomura
Y
Y
Segawa
M
M
Takagi
K
K
Senju
S
S
Matsushita
S
S
Nishimura
Y
Y
D019138:Antibodies, Blocking / Q000032:analysis; D017951:Antigen Presentation; D002675:Child, Preschool; D002999:Clone Cells; D018984:Epitopes, T-Lymphocyte / Q000032:analysis; D006681:HLA-D Antigens / Q000276:immunology*; D000949:Histocompatibility Antigens Class II; D006801:Humans; D007108:Immune Tolerance; D007223:Infant; D007231:Infant, Newborn; D008213:Lymphocyte Activation; D009157:Myasthenia Gravis / Q000276:immunology*; D010446:Peptide Fragments / Q000032:analysis; D010455:Peptides / Q000032:analysis / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000032:analysis / Q000276:immunology*; D011994:Recombinant Proteins / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*
D019138:Antibodies, Blocking; D018984:Epitopes, T-Lymphocyte; C416186:H-2O antigen; D006681:HLA-D Antigens; C046148:HLA-DO antigens; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D010455:Peptides; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins